1. Field of the Invention
The present application relates to a class of new intermediates for producing paliperidone, process of making these new intermediates, and process of making paliperidone.
2. Description of the Related Art
Previously known processes for producing paliperidone have low yields and produce large amounts of HCl gas as a by-product. In U.S. Pat. No. 5,158,952 (its European counterpart is EP0368388), a process is disclosed wherein 2-amino-3-benzyloxypyridine (I′) was reacted with 1.7 mole equivalents 2-acetyl-4-butyrolactone in the presence of 5.5 mole equivalents phosphoryl chloride in toluene. The reaction mixture was stirred for 5 hours at 90° C. Another 1.7 mole equivalents of 2-acetyl-4-butyrolactone were then added and the stirring was continued for 30 minutes at 90° C. The solution was allowed to stand overnight at 90° C. The whole was poured into crushed ice and treated with an ammonium hydroxide solution 25%. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2-propanol. The product was filtered off, washed with a mixture of 2-propanol and 1,1′-oxybisethane and dried at 50° C., yielding 20.5 mole equivalents (Yield: 62.3%) of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 141.1° C. See the scheme shown below.

The yield of this condensation reaction is low, and the higher amounts of lactone (about 3.4 mole equivalents) and POCl3 (about 5.5 mole equivalents) are needed to facilitate this reaction. In addition, POCl3 releases lots of HCl gas during decomposition. Furthermore, the reaction mixture containing the intermediate II needs to be purified by column chromatography to remove the unreacted 2-amino-3-benzyloxypyridine (I′) before further conversion to paliperidone.
Therefore, there is still need for a process of making paliperidone that is easy to operate, incurs low cost, and/or produces a high yield of product.